Abstract: Innate immune signaling requires careful coordination such that the adaptive immune system can be tailored to eradicate an offending pathogen. Too much signaling can result in autoinflammatory disease while too little signaling can result in immunodeficiency. Interestingly, immunodeficiency is often complicated by hyper- inflammatory states, and the maintenance of this inflammatory balance is particularly important in the intracellular pathogen recognition signaling system driven by the NOD2:RIPK2 complex. Loss-of-function polymorphisms in NOD2 cause decreased signaling in response to bacterial infection and predispose to Crohn?s disease, a disorder characterized by acute and chronic inflammation of the gastrointestinal tract. In contrast, gain-of-function NOD2 mutations, which cause increased signaling in response to bacterial infection, cause Early Onset Sarcoidosis, an inflammatory disorder characterized by uveitis and granulomatous inflammation in the mediastinum. Even WT NOD2 and WT RIPK2 influence inflammatory disease. As NF-?B regulated genes, NOD2 and RIPK2 expression and activity is heightened during inflammation, and hyperactivation of WT NOD2 and WT RIPK2 can drive the pathophysiology of diseases as diverse as multiple sclerosis, rheumatoid arthritis, asthma and inflammatory bowel disease. This therefore highlights the unique balance that must be maintained by both NOD2 and RIPK2 to maintain physiologic inflammation while avoiding pathologic inflammation. Our work under this grant has been directed at understanding the molecular basis for NOD2:RIPK2 signal transduction and to translate that work to clinical medicine. In the current grant application, we aim to study the interaction of the inflammasome?s interaction with the NOD2:RIPK2 signaling pathway, the ubiquitin dynamics regulating this pathway and a novel mechanism of downregulation of this pathway.